Cancers Protect Themselves Against Their Own Mutations

Most cancerous tumors accumulate thousands of potentially protein-damaging mutations over time, yet they mysteriously continue to thrive.¹ Now, a new computational study helps explain how that is possible: Tumors with a large number of mutations upregulate genes that minimize misfolded proteins to protect them from their own mutations.²

“[These mutations] very likely accrue over decades, and the cancer cells need a way to cope,” said computational biologist Christina Curtis from Stanford University, who coauthored the study. 

     

To reveal that coping mechanism, Curtis and her team explored the gene expression of nearly 10,300 human tumors across 33 cancer types catalogued in the Cancer Genome Atlas database.³ They found consistent upregulation of chaperone proteins and the proteasome, which respectively prevent and degrade misfolded proteins. 

Next, the researchers validated their findings using cell line data from the Cancer Cell Line Encyclopedia.⁴ The cell lines showed similar expression patterns, and when the team calculated the effect of knocking down the upregulated genes, higher mutational loads correlated with reduced cell viability. These results suggest that the gene upregulation protects tumors.

For Curtis, this discovery signals a general vulnerability in many tumors that could be exploited, for example by using chaperone and proteasome inhibitors. Scientists developed such drugs decades ago, but this new information might help target them to the tumors that will be most vulnerable.

Cancer geneticist Ekta Khurana from Weill Cornell Medicine, who was not involved in the study, said that this was an exciting finding that looked beyond the mutations that help cancers grow. “[It] beautifully shows that broadening our perspective can lead to not just insights about how cancers evolve, but actual therapeutic opportunities.”